Synergistic Stromal Remodeling and Dual Chemo-Immunotherapy in Pancreatic Cancer: A Two-Stage Losartan-Primed followed Nanocarrier Strategy for Tumor Microenvironment Reprogramming

Pancreatic ductal adenocarcinoma (PDAC) is marked by a dense, fibrotic stroma that hinders drug delivery and promotes an immunosuppressive microenvironment. We developed a two-stage therapeutic strategy (LIGEL) that combines losartan-mediated stromal preconditioning with the targeted delivery of a hybrid nanocarrier (IGEL) co-loaded with gemcitabine and IL-12 circRNA. The efficacy of this approach was evaluated in vitro and in vivo, with RNA sequencing used to explore transcriptomic changes in the tumor microenvironment after treatment. Losartan pretreatment significantly reduced extracellular matrix deposition and cancer-associated fibroblast activation, enhancing cellular uptake and tumor penetration. This resulted in notable tumor growth inhibition, prolonged survival, and minimized gemcitabine-associated systemic toxicity. Transcriptomic analysis revealed tumor cell depletion and immune microenvironment activation. These findings highlight the potential of losartan-primed nanotherapy to reprogram the tumor microenvironment and improve the efficacy of combined chemotherapy-immunotherapy.